葛根素注射液对糖尿病家兔溶血作用研究

目的 研究葛根素注射液在正常和糖尿病家兔体内给药后的溶血规律,为临床安全合理用药提供依据。方法 采用四氧嘧啶复制1型糖尿病家兔模型,并与正常健康家兔进行对照,设置10、20、40 mg·kg-1体质量三个剂量组,每周期给药10 d,在给药前以及每个给药周期的第2、4、6、8、10天分别采血,观察红细胞形态并比较体外溶血差异。结果 正常家兔和糖尿病家兔红细胞在给药后的溶血率较之给药前均有升高,糖尿病组的溶血率高于正常组,在给药后6～8 d溶血率升至最高。溶血率与给药剂量和给药时间成正相关。结论 临床使用葛根素注射液,给药时间应控制在8 d以内,若需长时间用药,需要在每个用药周期后间隔4～5 d的清洗期,以保证用药安全性,避免发生溶血反应。     

The disposition of cytosine arabinoside and its metabolite after single doses to rabbits

Cytosine arabinoside (ara-C) is rapidly deaminated in vivo to ara-U by cytidine-deoxycytidine deaminase. The purpose of this study was to determine the contribution of the deamination pathway to the overall clearance of ara-C after a single dose to rabbits, as well as to determine the pharmacokinetics of ara-U itself. Male rabbits were cannulated in the marginal ear vein and received a single IV bolus dose (50 mg kg-1) of either ara-C (n = 10) or ara-U (n = 10). Blood samples were collected for up to 24 h. One week later, the rabbits received the opposite treatment. Plasma samples were analyzed by reversed-phase HPLC. The plasma clearance of ara-C (8.16 +/- 2.43 ml min-1 kg-1) was significantly higher than the clearance of ara-U (5.66 +/- 2.59 ml min-1 kg-1). The volume of distribution of ara-C was 0.64 +/- 0.16 l kg-1 (mean +/- SD) and was significantly smaller (p less than 0.05) than that of ara-U (1.22 +/- 0.70 l kg-1). As a result, the elimination rate constant of ara-C was significantly larger than that of ara-U (0.602 +/- 0.097 h-1 vs 0.258 +/- 0.05 l h-1). In the rabbits that received both treatments (n = 7), the fraction of the ara-C dose metabolized to ara-U (fm) was 0.53 +/- 0.20. Qualitatively, the pharmacokinetics of ara-C and ara-U resemble those in humans. This study provides the basis for further work into the modulation of ara-C disposition either by ara-U or other agents.     

Ocular pharmacokinetics of verapamil in rabbits

Previously, it had been demonstrated that cataract in diabetic rats can be prevented by systemical administration of the calcium channel blocker verapamil. In addition to that, 0.125% verapamil eye drops were found to significantly reduce the intraocular pressure in ocular hypertensive human subjects. The purpose of this study was to investigate the ocular penetration and elimination of verapamil after topical administration of the drug in rabbits. Two drops of a 0.125% aqueous solution of RS-verapamil hydrochloride (corresponding to a total dose of 125 μg RS-verapamil hydrochloride) were administered into the conjunctival sac. Aqueous humor and blood samples were taken at different times after administration and analysed for drug concentration by combined gas chromatography-mass spectroscopy. Following the instillation of 0.125% verapamil eye drops in a total dose of 125 μg RS-verapamil, mean (± SEM) aqueous humor peak levels of 1607 ± 272 ng/ml were achieved after 20 min. Mean half-life for the elimination from the aqueous humor was 33 min. Topical application of verapamil produced very low serum peak concentrations (10.5 ± 1.3 ng/ml). The results of our study demonstrate that topically administered verapamil readily penetrates into the anterior chamber leading to aqueous humor drug levels in the μM range without producing serum levels that are high enough to cause cardiovascular side effects. Received: 9 September 1997 / Accepted: 18 November 1997     

The influence of cimetidine on the pharmacokinetics of diltiazem and its main metabolite in rabbits

The purpose of this study was to investigate the pharmacokinetic alteration of diltiazem and its main metabolite, deacetyldiltiazem, after oral administration of diltiazem in rabbits with or without cimetidine co-administration. The area under the plasma concentration-time curve (AUC) of diltiazem was significantly elevated in rabbits pretreated with cimetidine, suggesting that the oral clearance, an index of intrinsic clearance, may be decreased by the cimetidine treatment. Consistent with the increased AUC by the treatment, peak plasma concentration (Cmax) for diltiazem was also elevated. Apparent volume of distribution normalized by the bioavailability (Vd/F) of diltiazem increased significantly in rabbits pretreated with cimetidine increased. Taken together with the fact that the first pass metabolism for diltiazem is the primary determinant for the oral bioavailability, these observations indicate that increases in the oral clearance and Vd/F may be a manifestation of the decreased first pass metabolism. Consistent with the hypothesis, the AUC of deacetyldiltiazem was significantly decreased in rabbits with cimetidine treatment. Ratio of deacetyldiltiazem to total diltiazem in the plasma was significantly decreased in rabbits with cimetidine treatment. These observations suggested that the metabolism of diltiazem to deacetyldiltiazem was reduced by cimetidine treatment and that the dosage of diltiazem should be adjusted when the drug is co-administered chronically with cimetidine in a clinical setting.     

The effect of the fat content of food on the pharmacokinetics and pharmacodynamics of SDZ FOX 988, an antidiabetic agent,in the dog

SDZ FOX 988 (FOX 988) is being developed for the treatment of type II diabetes. The objective of this study was to examine the effect of the fat content of food on the pharmacokinetics and pharmacodynamics of FOX 988 following oral administration in the dog. In a randomized, cross-over design, four dogs received a single 10 mg kg^?1 dose of ¹⁴C-FOX 988 suspension concomitantly with food containing 10% fat or 40% fat, or with the 10% fat food at 4 h post-dose. Serial blood, urine, and fecal samples were collected for 96 h and analyzed for total radioactivity. Blod concentrations of 53–450, the active metabolite of FOX 988, were also determined. Serum concentrations of β-hydroxybutyrate and glucose, pharmacological markers for the antidiabetic effects, were measured serially for 24 h after dosing. The animals receiving the low-fat meal at dosing and at 4 h post-dose exhibited similar extents of absorption, as shown by similar AUC values and urianry radioactivity recovery. Administration of the high-fat meal at dosing significantly enhanced the absorption of FOX 988 and resulted in high blood concentrations of 53–450. However, no significant differences in the pharmacological activity of the drug were observed among the three treatments.     

芍药甙在兔和大鼠体内的药动学研究

兔iv25mg·kg~(-1)芍药甙后,血药浓度—时间曲线符合二室模型。药动学参数为T_(1/2α)=5.93min,T_(1/2β)66.02min,V(?)=516.8ml·kg~(-1),CL=6.11ml·kg~(-1)·min~(-1)。兔ig250mg·kg~(-1)芍药甙,生物利用度为F=7.24％±4.15％,T_(max)=77.4min,C_(max)=21.57mg·L~(-1)大鼠ig550mg·kg~(-1)芍药甙,24h内粪、尿排泄量及iv55mg·kg~(-1)7h内胆汁排泄量分别占给药量的10.61％、1.08％、864％。离体肝脏灌流结果提示:芍药甙在肝内代谢少.     

非线性混合效应模型法计算1型糖尿病大鼠环孢素药代动力学参数

目的 研究糖尿病对环孢素(Ciclosporin, CsA)体内药物代谢动力学的影响。方法 大鼠腹腔注射65 mg·kg^-1链脲菌素(STZ)建立1型糖尿病大鼠模型。造模5周后通过荧光偏振免疫分析(FPIA)法检测大鼠灌胃环孢素(10 mg·kg^-1)后全血中的环孢素浓度,采用非线性混合效应法(Nonlinear mixed effect model, NONMEM)建立药物代谢动力学模型,贝叶斯(Bayes)反馈法获取个体参数并比较。结果 STZ注射1周后,大鼠空腹血糖超过11.1 mmol·L^-1,确认1型糖尿病大鼠造模成功。造模5周后,糖尿病大鼠的血糖显著增高。给药后,环孢素在大鼠体内呈现一房室模型,群体典型值及个体间差异(Between Subject Variability, BSV)分别为：CL/F=0.525 L·h^-1, BSV=32.1%;V/F=5.18 L, BSV=35.6%; Ka=1.82,BSV= 71.1%。正常组与糖尿病组大鼠CL/F无显著性差异(P>0.05);V/F无显著性差异(P>0.05);Ka有显著性差异(P<0.05) 。结论 1型糖尿病大鼠灌胃环孢素的吸收速率常数显著改变,且存在较大的个体间差异,提示糖尿病状态下会影响环孢素的吸收。     

Distribution and pharmacokinetics of five Rhubarb anthraquinones in rabbits and rats

The main active components of Rhubarb are anthraquinones (AQs), most of which are glycosides and others are free. The concentrations of AQs derivatives (rhein, aloe-emodin, emodin, chrysophanol and physcion) in plasma and homogenate were assayed with a high performance liquid chromatography (HPLC) method. The pharmacokinetic parameters and distribution of Rhubarb AQs in rabbits or rats were studied after administrationof different formulas. Elimination of AQs was fit to a two-compartment model in rats and rabbits. There were no significant difference in the main pharmacokinetic parameters between rhein and AQs in rats. AQs were distributed progressively in the kidney, liver, blood, and heart. The AQs were mainly composed of rhein in vivo and was excreted by the kidney. For formulas that contained Rhubarb, rhein could be used as a probe for in vivo pharmacokinetic studies.     

硫酸依替米星与哌拉西林合用兔体药代动力学研究

对依替米星 (etimicin,ETM)与哌拉西林 (piperacillin,PIPC)兔体合用药动学进行了研究。采用自身交叉试验 ,以微量微生物法 (IMM)检测血、尿中 ETM浓度 ,检测菌为短小芽胞杆菌 ,药时数据经 3P87软件处理。结果证明 :(1)兔体 ETM单用及与 PIPC合用时药时曲线均符合二房室开放模型 ;(2 )单用组和合用组的 V(c)、t1 /2α、t1 /2β、K2 1 、K1 0 、K1 2 、AUC、Cls等药动学参数分别为 :0 .2 738和 0 .2 747L / kg;0 .310 0和 0 .3315 h;1.6 86 5和 1.6 882 h;1.40 81和 1.36 111/ h;0 .6 6 96和 0 .6 6 35 1/ h;0 .6 2 0 7和 0 .5 6 5 6 1/ h;38.32 71和 38.6 410mg·h/ L;0 .1834和 0 .182 3L/ h;(3) 12 h尿药回收率分别为 87.46 %和 87.18%。两组之间其它药动学参数均无显著性差异 (P>0 .0 5 )。表明两药合用时 PIPC对 EMT兔体内的药动学无显著影响 ,具有一定优越性。本结果为临床联合用药提供了依据。     

The effect of short-term dipyrone administration on cyclosporin pharmacokinetics

Background: A large number of drugs have been shown to affect the metabolism of cyclosporin A (CSA) and, since cyclosporin is characterized by a narrow therapeutic range, the consequences of such drug interactions may often be of clinical importance. Objective: To evaluate the effect of short-term administration of dipyrone on steady state CSA pharmacokinetics. Methods: Six kidney- and two heart-transplanted patients on chronic CSA therapy participated in this study, which consisted of two 4-day study periods separated by 3-week washout periods. The patients received, in addition to their usual drugs, dipyrone 500 mg or placebo t.i.d., as identical-looking tablets, and the order of administration was randomized. CSA concentrations were measured in whole blood by means of radio-immunoassay (CYCLO-Trac SP) daily during the study periods and periodically over 24 h on the fourth study day. Results: CSA concentrations over time were reduced after dipyrone (ANOVA, P < 0.01), but statistical significance was noted only at 2, 4, 5 and 10 h after drug intake (P < 0.05). Peak CSA concentration was not altered by dipyrone, but the time required to reach maximal concentration was longer with dipyrone treatment than with the placebo (3.8 ± 2.6 h vs 2.1 ± 0.6 h, P < 0.05). No consistent changes were noted for CSA trough level, elimination half-life and area under the concentration–time curve from 0 h to 12 h. Separate analysis of the kidney transplanted patients yielded similar results. Conclusions: Short-term administration of dipyrone is associated with a mild decrease in CSA blood concentration, which is most prominent in the first few hours after drug intake. In practice, no dose adjustment of CSA seems to be indicated during a short course of dipyrone treatment. Received: 13 January 1999 / Accepted in revised form: 15 March 1999     

液相质谱串联法同时测定舒尼替尼及其活性代谢产物SU12662在BABL/c裸鼠血浆中的浓度及其药物动力学研究(英文)

本研究建立并验证了一种灵敏、快速、简单的液质联用方法,用于同时测定BABL/c裸鼠血浆中舒尼替尼及其活性代谢产物SU12662的药物浓度。血浆样品采用蛋白沉淀方法处理,并使用帕唑帕尼作为内标。采用C18反相柱进行分离,流动相为10 mM甲酸胺–乙腈(65:35,v/v,pH 3.25),流速0.5 m L/min。所有化合物均采用电喷雾电离源,正离子方式检测。舒尼替尼及SU12662的最低定量下限均为0.5 ng/m L,线性范围均为0.5–1000 ng/m L(r>0.99)。该方法对舒尼替尼及SU12662的测定均具有良好准确度以及可靠的日内、日间精密度,方法稳定性良好,无明显基质效应。此方法成功用于BABL/c裸鼠口服20 mg/kg舒尼替尼的药物代谢动力学研究。     

Population pharmacokinetics of gliclazide in normal and diabetic rabbits

Gliclazide is a second‐generation sulphonylurea drug widely used in the treatment of type 2 diabetes. However, there is no single report to describe the population pharmacokinetics of gliclazide in animal models. This study was aimed to evaluate the population pharmacokinetics (PK) of gliclazide in normal and alloxan‐induced diabetic rabbits using nonlinear mixed effects modeling. A total of 90 New Zealand white rabbits were administered with three doses (4.13, 8.27 and 16.53 mg/kg b.wt) of gliclazide by an oral route. Blood samples were collected up to 24 hr and the gliclazide concentrations in rabbit were determined using the HPLC method. The non‐compartmental and classical compartmental PK analyses were performed using Phoenix WinNonlin. Population PK analysis of gliclazide was performed using nonlinear mixed‐effects model software NONMEM and Phoenix NLME considering the weight, age, sex, health and dose as covariates. The final population values for clearance (CL), volume of distribution (V) and the absorption rate constant (k_a) were 5270 ml/hr, 55700 ml and 0.708 hr^?1, respectively. The inter‐individual variability in gliclazide CL, V and k_a was 16.3%, 14.9% and 26.5%, respectively. There was no significant difference between NONMEM and Phoenix NLME pharmacokinetic results. The visual predictive check and bootstrap analysis confirmed the predictive ability, model stability and precision of the parameter estimates from this model. This population PK model demonstrated that gliclazide pharmacokinetics is best described by one‐compartment model with first‐order absorption in rabbits. Body weight is a covariate that significantly influences gliclazide kinetic disposition in rabbits.     

头孢唑林对阿米卡星在兔体内的药动学影响

采用微量微生物法对阿米卡星（ＡＭＫ）单用及与头孢唑林（ＣＥＺ）合用后兔体内ＡＭＫ血药浓度进行测定,药时数据用ＭＣＰＫＰ软件经ＩＢＭ 计算机处理,并对两组药动学参数进行了统计学处理,结果表明ＣＥＺ对ＡＭＫ的药动学有显著的影响。     

The effect of chloroquine on the pharmacokinetics and metabolism of praziquantel in rats and in humans

It is likely that a proportion of people treated with the anti-schistosomicidal drug praziquantel (PZQ) is also taking other drugs such as chloroquine (CHQ), a widely used anti-malarial. The effect of CHQ on the pharmacokinetics and metabolism of PZQ in rats and in humans was therefore studied. CHQ decreased the bioavailability of PZQ and reduced its maximum serum concentrations to a significant extent in rats and in humans. The clearance was increased to a statistically significant extent in rats but not in humans because of the wide interindividual variation. The effect of CHQ on PZQ pharmacokinetics was unexpected since drugs that inhibit hepatic drug metabolism usually increase the bioavailability of PZQ. We found that CHQ inhibits non-competitively the metabolism of PZQ to its major metabolite, 4-hydroxy-praziquantel, with a K_i of 1.65 mM in rat hepatic microsomes. Maximum concentrations attained by CHQ in serum, however, are low compared to the K_i value and significant inhibition is therefore unlikely in vivo. The explanation for CHQ's effect on the pharmacokinetics of PZQ may be due to other effects of CHQ rather than to a direct effect on drug-metabolizing enzymes.     

The effect of grapefruit juice on the pharmacokinetics of orally administered verapamil

Objective: To investigate the effect of grapefruit juice (GJ) on the pharmacokinetics of orally administered verapamil in hypertensive patients. Methods: Ten hypertensive patients on chronic verapamil treatment participated in a two-day study. On day 1 200 ml of water was given 1 hour before, and together with the morning verapamil dose; on the day 2, water was replaced by GJ in the same order. Serial blood samples were collected and the concentrations of verapamil and its main dealkylated metabolite (D-617) were determined by high-performance liquid chromatography (HPLC). The area under the concentration versus time curve of verapamil (AUC_v) and its metabolite D-617 (AUC_M) were calculated before and after GJ ingestion. The peak serum concentration (C_max) and the time until its appearance (t_max) were also determined. Results: GJ did not affect C_max, t_max, AUC_v or AUV_m. The AUC_v/AUC_m ratio (AUC_R) was slightly, but significantly, increased after GJ (1.67 vs 1.92). Conclusions: A single administration of GJ with short-acting verapamil has no significant effect on the pharmacokinetics, of verapamil. Received: 2 October 1997 / Accepted in revised form: 2 March 1998     

Circadian changes in pharmacokinetics of sulfamethoxazole administered orally to rabbits

Circadian variations of sulfamethoxazole pharmacokinetics were studied after a single oral administration of sulfamethoxazole, 50 mg/kg, to rabbits at 09:00 (a.m.) and 22:00 (p.m.). The profiles of plasma sulfamethoxazole concentration showed from 6 h to 24 h significant statistical difference (p<0.05) between 09:00 and 22:00. The half-life (t(1/2)) was significantly shorter in the morning (11.2 +/- 3.2 h) when compared to the nighttime (15.4 +/- 3.5 h) (p< 0.05). The AUC was significantly decreased in the morning (1325 +/- 264 microg/ml x h) than that in the nighttime (2059 +/- 379 microg/ml x h) (p<0.05). Total body clearance (CLt) was significantly higher when sulfamethoxazole was given in the morning (6.65 +/- 0.23 ml/min) versus in the nighttime (4.28 +/- 0.20 ml/min) (p<0.05).     

Multivariate models of health-related utility and the fear of hypoglycaemia in people with diabetes

ABSTRACT

Aim: The aim was to statistically model the degree of fear of hypoglycaemia experienced by people with diabetes, and then model the resulting change in health-related utility associated with differing severity and frequency of hypoglycaemia.

Methods: The study used pooled data from two previous postal surveys among subjects with confirmed diabetes conducted in Cardiff, UK (n = 1305 responses). The fear of hypoglycaemia was characterised using the Hypoglycaemia Fear Survey (HFS [eight question worry sub-scale only]), and health-related utility using the EQ5D_index. The data were then analysed using univariate and multivariate analysis.

Results: Following detailed preliminary analysis, a two-stage approach was used since fear was important when estimating the EQ5D_index. Fear was then modelled as a function of the severity and frequency of hypoglycaemia while controlling for other factors such as diabetes-related complications. Each severe hypoglycaemic event resulted in a change of 5.881 units on the HFS. One or more symptomatic hypoglycaemic events over the same period results in a corresponding change of 1.773 units on the HFS. A 1 unit increase on the HFS results in a 0.008 unit decrease on the EQ5D_index.

Conclusion: While controlling for other factors, the fear of hypoglycaemia was an important determinant of health-related utility. The magnitude of fear of hypoglycaemia was associated with the severity and frequency of hypoglycaemia. Hypoglycaemia was associated with a considerable decrement in health-related utility as a function of increased fear. Measures should be taken to minimise the severity and frequency of hypoglycaemia.     

The effect of body weight on dalteparin pharmacokinetics A preliminary study

Aim: To investigate whether there were significant differences in the volume of distribution (V) and clearance (CL) of dalteparin in obese versus normal-weight patients, and thereby determine whether dosing of dalteparin should be based on total body weight, lean body weight or an adjusted body weight in obese patients. Methods: Patients (ten obese and ten normal weight) treated with dalteparin were matched for age, gender, lean body weight and creatinine CL. Two steady-state plasma dalteparin concentrations were taken from each patient and assayed in duplicate. The pharmacokinetic values of V and CL were estimated, for each patient, using the Bayesian maximum a posteriori method with the program ABBOTTBASE. Results: The mean V in obese patients was approximately 60% larger than in normal-weight patients, but this was not statistically significant (P=0.11; two-tailed). The mean value of V (8.4 l) in the normal-weight patients was similar to that reported in the literature. The mean difference in values of CL (18% larger in obese patients) was not clinically or statistically significant. A poor correlation was seen between V and lean body weight (r ²=0.05). There was a moderate correlation between V and total body weight (r ²=0.52) and between V and adjusted body weight (r ²=0.55); adjusted body weight=[lean body weight + 0.4(total body weight – lean body weight)]. Total body weight and adjusted body weight provided a better correlation with CL (r ²=0.39, 0.32, respectively) than did lean body weight (r ²=0.01). Conclusion: These results suggest that doses of dalteparin in obese patients should be based on total body weight or an adjusted body weight, but not lean body weight. This study highlights some potential differences in the pharmacokinetics of dalteparin in individuals who are obese, and further work is necessary to quantify these differences in more detail. Received: 30 July 1999 / Accepted in revised form: 16 March 2000